title: Constitutive transduction of peptide transporter and HLA genes restores antigen processing function and cytotoxic T cell-mediated immune recognition of human melanoma cells.
abstract: Potentiation of immunogenicity of malignant cells by gene transduction provides a unique opportunity for immune targeting of human cancers in vivo. This approach is undoubtedly influenced by the ability of the malignant cells to process and present endogenously target epitopes on their cell surface for immune recognition by cytotoxic T lymphocytes (CTLs). In the present study, we have investigated potential immune-resistance pathways in human malignant melanoma by analyzing the major histocompatibility complex (MHC) gene expression and function in a panel of tumour cell lines. Our analysis showed that a large proportion of these cell lines consistently display a functional defect in the endogenous processing of CTL epitopes and are recognised poorly by specific T cells in spite of high levels of target antigen expression in the tumour cells. Molecular characterisation of this defect revealed that tumour cells under-expressed peptide transporters and surface-assembled MHC class I molecules, which constitute essential components of the class I processing pathway. Induction of peptide transporter and surface class I following treatment of these tumour cells with interferon gamma (IFN-gamma) suggested a transcriptional defect in the expression of antigen-processing genes. Endogenous processing function in these tumour cells was restored completely following simultaneous transduction of cells with peptide transporter and HLA class I genes. Our findings provide a rationale for focussing on strategies designed to improve antigen-processing function in tumour cells and, thus, may strongly influence future strategies for melanoma-specific immunotherapy.
authors.affiliation: The Cooperative Research Centre for Vaccine Technology, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: C A
authors.initials: CA
authors.lastname: White
authors.forename: S A
authors.initials: SA
authors.lastname: Thomson
authors.forename: L
authors.initials: L
authors.lastname: Cooper
authors.forename: P M
authors.initials: PM
authors.lastname: van Endert
authors.forename: R
authors.initials: R
authors.lastname: Tampe
authors.forename: B
authors.initials: B
authors.lastname: Coupar
authors.forename: L
authors.initials: L
authors.lastname: Qiu
authors.forename: P G
authors.initials: PG
authors.lastname: Parsons
authors.forename: D J
authors.initials: DJ
authors.lastname: Moss
authors.forename: R
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008545:Melanoma / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D016326:Extracellular Matrix Proteins; D015395:Histocompatibility Antigens Class I; D009419:Nerve Tissue Proteins; C073119:TAP1 protein, human; C071692:TAP2 protein, human; D007371:Interferon-gamma